Chronic pain affects over 100 million Americans annually. Opiates are the primary drugs that can treat chronic pain. However, these drugs produce severe unwanted side effects. There is clearly a large, unmet need for drugs that can produce analgesia with limited or no side effects. The peptide neuromedin U (NMU) has been shown to be an integral component of peripheral pain pathways. We have shown that knockout mice that do not express the neuromedin U receptor 2 (NMUR2) have reduced pain sensitivity in multiple pain models, whereas other physiological activity and responses in the animal appear normal. This provides evidence that NMUR2 is an important drug target and suggests that NMUR2 antagonists may be useful as analgesics. We have found through our drug discovery program several NMUR2 antagonists. We intend to quickly develop NMUR2 antagonists potent enough to conduct animal testing through additional screening of compounds with common structural features to those already identified. In this phase I grant, we propose to validate NMUR2 antagonists as novel analgesics. We intend to employ a standard drug development approach to achieve this goal. In Aim 1, we will use screening of compounds similar to the original hits to optimize our NMUR2 antagonists for increased potency and bioavailability. In Aim 2, these lead compounds will be tested in an array of nociceptive models to determine their in vivo efficacy and the types of pain most sensitive to these drugs. These studies will lay the foundation for the preclinical development of NMUR2 antagonists as analgesics in Phase II. This project seeks to validate NMU receptor 2 as a novel target for pain treatment, and start the development of the receptor antagonists as a new class of analgesics. [unreadable] [unreadable] [unreadable]